Abstract: The need for new therapeutic approaches: Conventional drug discovery is a lengthy and expensive process, taking decades and billions of dollars to get a drug from bench to bedside. Much of the costs incurred are at the pre-clinical stages, between drug design and synthesis to delineating the cellular “Mechanisms of Action” (MoA). Notably, there is a very high risk of failure, and only a very small proportion of therapeutic agents reach later-phase clinical trials. Accordingly, drug repositioning has become a valuable strategy aimed at fast-tracking treatments into clinical use and improving the chances of therapeutic success. A novel addition to this approach is connectivity mapping, which defines cell-specific transcriptional responses to small molecules in disease-dependent contexts. This commentary outlines how some of the latest innovations in connectivity mapping can be exploited for drug repurposing.